Idarubicin-anti-CD3: A new immunoconjugate that induces alloantigen-specific tolerance in mice

Mottram, PL; Han, WR; MurraySegal, LJ; Mandel, TE; Pietersz, GA; McKenzie, IFC

Author(s): Mottram, PL; Han, WR; MurraySegal, LJ; Mandel, TE; Pietersz, GA; McKenzie, IFC;
Details: Publication Year 1997-09-15,Volume 64,Issue #5,Page 684-690
Journal Title: TRANSPLANTATION
Publication Type: Journal Article
Abstract: Background. In testing new anti-CD3 agents for transplantation tolerance induction, an anti-CD3 monoclonal antibody was used as a carrier for the cytotoxic drug idarubicin (IDA). Methods. Anti-CDS (KT3) was covalently coupled with IDA, producing the IDA-KT3 immunoconjugate, which was tested for specificity by fluorometry and for inhibition of proliferation of CD3(+) E3 cells ([H-3]thymidine uptake). KT3 and IDA-KT3 were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice with hearts surviving >100 days were challenged with donor and third-party (C57BL/6) skin. Results. Conjugation to IDA did not reduce binding of KT3 to E3 cells, although the toxicity of IDA was reduced by conjugation. In BALB/c to CBA cardiac allografts (rejected in 12-17 days), both KT3 and IDA-KT3 (0.25-0.5 mg/20 g mouse i.p. at the time of transplantation) induced tolerance. Hearts survived >100 days and skin graft challenge showed indefinite survival of donor grafts but not third-party grafts. KT3 was less toxic, as measured by tumor necrosis factor-a release and blood glucose levels, than equivalent dosages of 145-2C11. At lower dosages (0.1 mg/20 g mouse), KT3-treated animals rejected BALB/c allografts in 15 to 19 days, but IDA-KT3 induced long survival (>100 days) and donor-specific tolerance in 5 of 6 mice. Conclusions. Coupling IDA to anti-CD3 reduced the in vivo toxicity of IDA and improved the immunosuppressive performance of KT3, reducing the side effects seen with other anti-CD3 agents. IDA-KT3 is a new, effective, nontoxic tolerogen in this donor-recipient combination.
Publisher: WILLIAMS & WILKINS
Keywords: ANTI-CD3 MONOCLONAL-ANTIBODY; NONOBESE DIABETIC MICE; FETAL PIG PANCREAS; TRANSPLANTATION TOLERANCE; ALLOGRAFT-REJECTION; MOUSE; IMMUNOSUPPRESSION; MODEL; HYPERSENSITIVITY; IMMUNOTOXINS
Publisher's Version: https://doi.org/10.1097/00007890-199709150-00004
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 1997-09-15 12:00:00